Implantable polymeric materials capable of being degraded and absorbed by the body have been used in medicine for many years. For example, implantable devices can be pre-seeded with a desired cell type, and used as structural supports or scaffolds for guiding tissue regeneration. One example is the regeneration of cartilage tissue using a degradable fiber mesh pre-seeded with chondrocytes as described in U.S. Pat. No. 5,041,138 to Vacanti et al. However, implantation of the scaffolds requires surgical intervention which presents disadvantages, such as the risk of infection and the need for invasive and painful procedures.
Suspensions of liquid hydrogel-cell compositions, which solidify in vivo following administration, have also been described as useful for the delivery of cells to a tissue surface in need of repair. See, for example, U.S. Pat. No. 5,944,754 to Vacanti. However, controlled delivery and containment of a liquid system within a particular area is difficult, and the liquid can spread to areas other than the implant site prior to solidification.
As such, a need exists for improved compositions and methods for administering live cells to a host to provide a therapeutic effect in the host, such as tissue regeneration.
The invention relates to an improved method for administering live cells to a patient and compositions useful in the method. The composition comprises live cells and biocompatible, biodegradable polymer microparticles. The cells and microparticles of the cell/microparticle composition can be contacted immediately prior to administration, or can be contacted in culture for a specified period of time prior to administration. In the method of the invention, an effective amount of the cell/microparticle composition is administered to a patient in need thereof by injection to a treatment site to provide a therapeutic effect in the patient. The therapeutic effect can be, for example, the formation of new tissue at the treatment site, or the production and secretion of a biologically active secretory molecule at the treatment site. The therapeutic effect resulting from injection of the cell/microparticle composition into a treatment site, is determined by the type of cell present in the composition.
Alternatively, the cell/microparticle composition of the invention can be used to generate in vitro tissue having a specific shape which can then be implanted in the patient at an implantation site to replace damaged tissue. The cell/microparticle composition is placed in a cell culture chamber having a desired shape. As the cells proliferate and adhere to the surfaces of the individual microparticles, a coherent mass of tissue having the shape of the culture chamber is formed. The formation of this coherent mass is referred to herein as xe2x80x9csinteringxe2x80x9d. Sintering differs from other methods of preparing tissue in specific shapes, since it is the combination of cells and polymer microparticles which provide the matrix responsible for the shape of the resulting tissue rather than the polymer alone.
In a specific embodiment, the composition and method of the invention can be used for generating new tissue growth at a treatment site in a patient in need of tissue regeneration. The method for generating new tissue growth in a patient in need thereof comprises administering to the patient by injection into a treatment site an effective amount of a composition comprising biocompatible, biodegradable polymer microparticles and live cells capable of generating new tissue. The cells can be, for example, hepatocytes for the generation of liver tissue or chondrocytes for the generation of cartilage tissue. In a preferred embodiment, the cells are chondrocytes which generate cartilage tissue. In a more preferred embodiment, administration of the chondrocyte/microparticle composition is into the articular space of a joint of the patient.
As such, in a preferred embodiment, the invention relates to a method of generating new cartilage tissue in a patient in need thereof comprising administering by injection to a treatment site of the patient a composition comprising live chondrocytes and biocompatible, biodegradable polymer microparticles. The method and composition can be used for the treatment of cartilage deficiencies, defects, voids and conformational discontinuities in a patient.
In a further embodiment, the composition of the invention can be used in a method for secreting a biologically active secretory molecule in a patient in need of said molecule. The patient can be a mammal, such as a human. The method for secreting a biologically active secretory molecule in a patient in need of said molecule comprises administering to the patient by injection into a treatment site of the patient an effective amount of a composition comprising biocompatible, biodegradable polymer microparticles and live cells, wherein said cells are capable of secreting the biologically active secretory molecule.
In a particular embodiment, the cells are live pancreatic islet cells which secrete insulin. The composition comprising pancreatic islet cells and biocompatible, biodegradable polymer microparticles can be administered to the pancreas or other suitable treatment site of the patient. As such, the invention relates to a treatment for diabetes.
In another preferred embodiment, the cells are dopaminergic cells capable of secreting dopamine, such as PC-12 cells, adrenal chromaffin cells and fetal nigral primordia cells. The composition comprising live dopaminergic cells and biocompatible, biodegradable polymer microparticles can be administered to the striatum or other suitable treatment site of the patient in need thereof. Therefore, the invention relates to a treatment for Parkinson""s disease.
In a particular embodiment, the composition comprising live cells and biocompatible, biodegradable polymer microparticles further comprises a biologically active agent. In a preferred embodiment, the biologically active agent is incorporated into the microparticle. The biologically active agent can be, for example, factors which modulate cell growth, such as factors having tissue regeneration inductive properties, for example, growth factors and differentiating factors, for example, morphogenic proteins; a cytokine; an extracellular matrix molecule; an antimicrobial agent; an anti-inflammatory agent; an immunosuppressive agent, cells which support the therapeutic effect of the administered cells or combinations thereof. Incorporation of the biologically active agent into the microparticles of the cell/microparticle composition provides a sustained delivery of the biologically active agent at the treatment site. It is preferred that the biologically active agent enhances the primary therapeutic effect resulting from administration of the live cell/microparticle composition.
The composition and methods of the present invention provide a means for eliciting a therapeutic effect in a patient in need thereof by administering a composition comprising lives cells and a biocompatible, biodegradable polymer microparticle. Advantageously, the composition permits the administration to be by injection which obviates the need for an open surgical intervention to permit exposure of the treatment area and the disadvantages associated with open surgery (e.g., pain, infection, recovery time and cost). In addition, the microparticles of the composition can have incorporated therein a biologically active agent thereby providing at the treatement site a sustained release of an agent which can be complementary to or enhance the primary treatment.
Advantages of the cell/microparticle composition are also realized when the composition is used to generate tissue in vitro having a specific shape. That is, sintering offers advantages over known methods of shaped tissue formation since a greater number of cells can be initially loaded into the culture chamber of a specified shape, thereby providing the needed tissue in a shorter period of time.